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Total Synthesis of Sporolide B

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Total Synthesis of Sporolide B Kanai's Lab Literature Seminar (B4 part) Nov. 10th 2010 Junya Kawai (B4) Total Synthesis of Sporolide B Isolation: from Salinospora tropica (a marine actinomyceta), and it also produces salinosporamide A, a potent inhibitor of the 20S proteasome. Structure: determined in 2005 (Fenical et al., Org. Lett., 2005, 7, 2731-2734) 7 rings, 10 stereogenic centers, and 22 out of 24 carbons are either oxygenated or sp2 hybridized. Including highly substituted indane system, a 1,4-dioxane ring, an epoxy cyclohexenone hemiacetal, and 13-membered macrolide moiety. Difference between sporolide A and B is only the location of chlorine atom on the benzenoid structure. Biological activity: None (but the precursor enediyne compound is considered to have an antitumor activity) Synthetic study: K. Gademann et al., Synthesis, 2010, 4, 631-642 (Biomimetic method) Total synthesis: K. C. Nicolaou et al., Angew. Chem. Int. Ed. 2009, 48, 3449-3453 (Sporolide B ) K. C. Nicolaou et al., J. Am. Chem. Soc. 2010, 132,11350-11363 (Sporolide B, 9-epi-sporolide B) Synthesis of sporolide A has never been reported. Contents 1. Biomimetic approach 1-1. Hypothetical biosynthesis of sporolides 1-2. Bergman cycloaromatization 1-3. Nucleophilic addition to p-benzyne 1-4. Gademann's synthetic study 2. Nicolaou's approach 2-1. Retrosynthetic analysis 2-2. Hetero [4+2] cycloaddition 2-3. Regioselective [2+2+2] cycloaddition 2-4. Model studies about cycloaddition 2-5. Total synthesis of sporolide B salinosporamide A Angew. Chem. Int. Ed., 2010, 49, 2 Chem. Soc. Rev., 2009, 38, 2993 1 1. Biomimetic approach Moore et al., PNAS, 2007, 104, 10376-10381 Moore et al., J. Am. Chem. Soc., 2008, 130, 2406-2407 1-1. Hypothetical biosynthesis of sporolides OH X OH OH O Y O Me O O OH O MeO O OH 1a: sporolide A (X=H, Y=Cl) 1b: sporolide B (X=Cl, Y=H) Bergman cycloaromatization OH OH OH O Me O O OH O O MeO O OH pre-sporolide pre-sporolide derived from 2 building blocks. 1-2. Bergman cycloaromatization O R. G. Bergman, Acc. Chem. Res., 1973, 6, 25-31 OH Basak et al., Chem. Rev., 2003, 103, 4077-4094 MeO Enz S O O O OH R3 OH O O R1 R1 R3 OH heat 2 3 R2 9-membered enediyne cyclohexenone epoxide R2 R4 R4 enediyne biradical intermediate (Z)-hex-3-ene-1,5-diyne "para-benzyne" OH O O O 1,4-cyclohexadiene SCoA HO SCoA (hydrogen donor) CCl4 Acetyl-CoA Malonyl-CoA H2N CO2H H Cl L-Tyrosine R1 R3 R1 R3 Biosynthesis toward pre-sporolide is catalyzed by several R2 R4 R R polyketide synthases encoded in spo gene cluster. 2 4 H Cl 2 Nicolaou et al., J. Am. Chem. Soc., 1988, 110, 4866 Niestroj et al., Eur. J. Org. Chem., 1999, 1-13 Sander et al., Angew. Chem. Int. Ed., 2003, 42, 502-528 , Distance between two terminal alkyne moiety is one of the key factors of reactivity. o Cyclization of 27 requires 200 C (t1/2 = 30 s), while 10- membered enediyne 62 proceeds smoothly even at 37oC. Fenical et al., Org. Lett., 2006, 8, 1024 9-membered enediynes are much more unstable. In nature, they are stabilized as chlomoprotein. Once separated from their protein complex, cyclization occurs rapidly. Buchwald et al., Science, 1995, 269, 814 Smith and Nicolaou, J. Med. Chem., 1996, 39, 2103-2117 Hydrogen atom abstraction from DNA leads to double-strand cleavage. So, many compounds possesing the enediyne structure has an antitumor activity. For cyclization of the acyclic enediyne, milder temperature can be adopted by bridging two alkyne moiety with transition metals. 3 1-3. Nucleophilic addition to p-benzyne O'Connor et al., J. Am. Chem. Soc., 2007, 129, 4795-4799 OH H OH Cl OH OH OH OH Slopes are clearly the same for all. O O Cl H Me O Me O O O OH O O OH O O MeO MeO Plausible mechanism O OH O OH sporolide A sporolide B Cyanosporaside A/B (products of S. pacifica), sprolide A/B were isolated as a 1:1 mixture of Cl-positional isomers. (No dihydro nor dichloro compound was detected.) Not radicalic pathway. The intermediate is haloaryl anion 7 (strong base) + How is only one Cl incorporated ? which can abstract D cation from DMSO-d6. The rate-limiting step is the cycloaromatization of 5 to 6. H/D LiX, pivalic acid Alternative mechanisms of cyclization can be excluded due to the reaction rate order. o DMSO-d6, 37 C Electron transfer from halide to p-benzyne can be rejected, because it is endothermic (>170 kJ/mol). 5 X 8 If the protonation occured before the chlorination, deuterium abstraction from DMSO-d6 would be unreasonable. A mix of transfers of an electron pair and a single electron.(10) Singlet biradical forms a new weak sigma bond between position 1 and 4, and halide approachs to the sigma antibond, then nucleophilic displacement occurs. (11, 12) Calculated study shows this halide addition step is exothermic, even in water. 8 is partially deuterated, even in absent of D2O. Thus, only one chlorine is introduced to either of the Reaction rate is just first order in [5](i.e. -d[5]/ dt = k[5]) two possible positions. and independent of [HA], [LiX], and the kind of halides. 4 1-4. Gademann's synthetic study Retrosynthetic analysis Biomimetic approach through Bergman cycloaromatization of 9-membered enediyne ring. If this route succeeded, a 1:1 mixture of both isomers could be obtained at the same time. The most challenging point is the high rigidity of 9-membered enediyne moiety. OH Me O O OH esterification OH X OH MeO O O X OPG OH O 30 OH Y Me H O OPG O O OH PGO O MeO HO O macrocyclization Y OH HO H OPG 1a: sporolide A (X=H, Y=Cl) 31 1b: sporolide B (X=Cl, Y=H) Bergman cycloaromatization H OPG OPG H O Acetylide H HO OH O O attack H OPG O O 32 33 Sonogashira cross-coupling 9-membered enediyne intermediate TBS OTBS O H O O TfO O H O 2-cyclopenten-1-one 34 35 5 Strategy 1) 9-membered enediyne ring K. Gademann et al., Synthesis, 2010, 4, 631-642 OH O O 12 steps CeCl3, LiCl, H O H O O LiN(SiMe2Ph)2 H O O -78 ~ 0oC O O O 2-cyclopenten-1-one 33 No TM Hirama et al., Chem. Lett., 1998, 27, 959 H OH OH CeCl3/LiN(TMS)2 (15eq.), Bergman THF (1mM); SM cycloaromatization O H 25oC, 3h up to 35% yield Lower temperature (<20oC), or higher concentration (5mM) only yielded dimer or oligomer. A large excess of CeCl3/LiN(TMS)2 was necessary to obtain TM in >10% yield. Thus, high temp. is required for intramolecular acetylide attack to enediyne, because of the rigidity of structure which came from two sp2 hybridized centers. But in this case, higher temp. made serious side reactions. Strategy 2) 9-membered diyne ring OPG OPG HO OH H Target structure; 2 HO OPG 9-membered ring diyne core without two sp hybridized centers (Less rigid structure than enediyne) 36 H O H OH H O H O H DMP 9 steps O 87% O 39 O O H 37 H O Target structure was not formed in various conditions. O 38 A. Yamashita et al., J. Am. Chem. Soc., 1975, 97, 891 Allenes are known to undergo isomerization to alkynes under strong base condition. So, they continued the synthesis using allene 39. 6 H H O H H H O O H H O O 40 O O : R = H 39 O R O 41: R = TMS 42: R = Me Strong base Lewis acid Temperature OH O H O H H O O O O O O O R O R O Cascade system toward formation of 9-membered ring failed under 22 conditions. H H H OTBS H OTBS KAPA H O O O O O O Simple isomerization also failed. O O R O O R 43: R = H 44: R = Me 45: R = TBS KAPA: Potassium 3-(aminopropyl)amide; prepared from KH & 3-aminopropylamine in situ. Yamishita et al., Chem. Commun., 1976, 959 Conclusion 9-membered enediyne ring is very difficult to construct due to the high rigidity of the structure. It is still uncertain whether the strategy of forming 9-membered diyne ring is promising or not. 7 2. Nicolaou's approach K. C. Nicolaou et al., Angew. Chem. Int. Ed., 2009, 48, 3449-3453 K. C. Nicolaou et al., J. Am. Chem. Soc., 2010, 132, 11350-11363 2-1. Retrosynthetic analysis Instead of biomimetic way, they proposed the approach through two unusual cycloadditions; Intramolecular hetero [4+2] cycloaddition, and ruthenium-catalyzed [2+2+2] cycloaddition. esterification OH Cl esterification (failed) OH (failed) O Cl OAc OH O O O Me OBn O O OH O Me O O MeO OBn OMe OAc O OH hetero [4+2] cycloaddition HO [2+2+2] cycloaddition 1b: sporolide B 2 AcO acetylide O addition esterification OAc O OBn O Me O Cl OBn OMe OH OTBS 4 3 O O O O OBn Me OH HO Li OH OBn OMe Cl 19 20 TMS OTBS 11 8 2-2. Hetero [4+2] cycloaddition (a) hetero 2e component (b) hetero 4e component X X X [4+2] X [4+2] Y Y Y Y X = O, Y = CR2 (carbonyl) X = O, Y = CR2 (enone) X = Y = NR X = Y = O (1,2-dicarbonyl) Nicolaou's Method [4+2] cycloaddition of 1,2-dicarbonyl moiety R1 O R1 R2 O R2 R R O R3 R4 O R4 R3 o-quinone (o-benzoquinone) 1,4-dioxane derivative Cycloaddition of substituted ortho-quinones has only been reported.
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